The nervous system is susceptible to DNA damage, and many human syndromes characterized by DNA repair defects feature with neuropathology ranging from profound neurodegeneration to microcephaly to brain tumors. Defective DNA damage responses have also been linked to Alzheimer's disease, and homeostasis of the aged brain requires effective DNA damage responses. Despite the importance of DNA repair in the nervous system, very little in vivo data are available that illuminate the molecular details of these processes in this tissue. Therefore, delineating the impact of defective DNA repair upon neural homeostasis is important for understanding neurological disease, and subsequently transitioning this knowledge into effective therapies. The goal of this proposal is to define the consequence of DNA damage in the nervous system with a particular emphasis on neurodegeneration that occurs when the key DNA damage transducer ATM is disabled. Inactivation of ATM leads to the neurodegenerative disorder ataxia telangiectasia, a syndrome characterized by defective DNA damage responses. We have shown that ATM is required for DNA damage signaling in the developing nervous system leading us to hypothesize that the neurodegeneration associated with A-T results from the eventual failure to eliminate DNA damaged neural cells during development. In this application, we will test a number of hypotheses that explore the role of ATM in the neural response to DNA double or single strand-breaks. Using mice in which critical components of these biochemical pathways are mutated, we will explore the impact of these DNA repair defects upon neural homeostasis with a focus on the involvement of ATM. Additionally, we will also establish the importance of the relationship between ATM and ATR signaling for brain homeostasis. The combined end-point of these experiments will be a greater understanding of the molecular processes required to prevent neurodegeneration and the tissue-specific consequences of defective DNA damage signaling in the developing nervous system. PUBLIC HEALTH RELEVANCE: Delineating DNA damage signaling and ATM function will be critical for understanding basic mechanism important for the development and maintenance of the nervous system. The experiments proposed in this application will be important for understanding how failure to respond to DNA damage in the nervous system can lead to incapacitating neurodegeneration. As many cancer therapies induce DNA damage, the results from this proposal may have significant therapeutic implications for understanding the mechanism of action of these drugs, particularly in the treatment of brain tumors.